The cellular response of the uterus to estrogens is a bi-phasic process involving first hypertrophy and, later, hyperplasia. The major objective of the proposed studies is to determine the underlying molecular mechanisms which produce these two responses. Our studies will focus on two major areas. The first is the role of estrogen receptor proteins and nuclear acceptor sites in cell growth and cell division. The second major area concerns key "metabolic" changes which lead to hypertrophy and hyperplasia, and how these changes result from the interaction of receptors and acceptors. In the first area we will study estrogen receptors and nuclear acceptor sites to determine if either undergoes modification following estrogen stimulation. We will study the structure of estrogen receptors and the binding affinities of receptors for estrogens at various times after estrogen administration to determine if any modifications take place which are responsible for producing hyperplasia. We will also study the number and nature of acceptor sites for receptor proteins to determine if nuclear acceptor sites which are involved in hyperplasia are under estrogen control. In the second major area we will study the effect of estrogens on uterine levels of cyclic AMP, cyclic GMP and specific uterine proteins, and determine if these parameters are involved in the control of hyperplasia as opposed to hypertrophy. A part of these studies will be to develop an in vitro system for studying estrogen stimulated DNA synthesis. BIBLIOGRAPHIC REFERENCES: Stancel, G. M., Thompson, W. J., and Strada, S. J. (1975), "Cyclic Nucleotide Phosphodiesterases in Uteriene Development," Molecular and Cellular Endocrinology3:283. Juliano, J. V. , and Stancel, g. M. (1976), "Estrogen Receptors in the Rat Uterus. Retention of Hormone Receptor Complexes," Biochemistry 15: 916.